Cancers avoid immune surveillance by actively suppressing the immune system. One method envisioned for counteracting this immunosuppression is through vaccination using epitopes of antigens that are either uniquely expressed or over-expressed by the tumor cells. For example, monoclonal antibodies (mAbs) that block signaling pathways, sequester growth factor and/or induce an immune response have been successfully implemented in the clinic to treat cancer and other diseases. Due to their favorable properties and clinical success, mAbs have been and continue to be the subject of intense protein engineering efforts. These efforts have yielded bispecific mAbs for improved targeting; single chain Fab variable fragments (scFvs), diabodies, and minibodies for better tumor penetration and blood clearance; and modified Fcs (through mutation or glycosylation) to alter immunostimulation or improve pharmacokinetic/pharmacodynamic properties. Likewise, mAbs have been reengineered to permit the site-specific conjugation of small molecules for improved delivery (e.g., ThioMABs) or to irreversibly bind to their antigen (e.g., infinite affinity mAbs). MAbs have also been developed to improve the circulation and presentation of bioactive peptides and other biologics (e.g., CovXbodies). Hetero-multimeric scFvs or scFvs or mAbs fused to avidin have also been developed for pre-targeted therapy and to improve the detection limits for tumor imaging.
Although mAbs can be effective and have some advantages over small molecule approaches, limitations such as adverse side effects due to off-target interactions or collateral damage due to long circulation times of radionuclide-conjugated mAbs indicates that there remains considerable room to improve their efficacy, including improved targeting and synergy. Therefore, enhancement of antibody and small molecule therapeutic efficacy would be useful and desired in the treatment of cancer and other diseases.